Interpretive Summary: A cluster of genes known as APOA1, APOC3, APOA4 and APOA5 code for important regulators of levels of blood lipids in the fasting state. However, the majority of lipid metabolism takes place in the hours after meal consumption and there is a paucity of knowledge about gene regulation during this time. With the aim to characterize possible regulators of lipid metabolism, we studied the effects of nine genetic variants during the immediate post-meal consumption period. Eighty-eight healthy young men were analyzed for genetic variants mapping to the four apolipoprotein (APO) genes listed above and these men were fed a meal of 60% fat, 15% protein, 25% carbohydrate. Serial blood samples were extracted for 11 hours after the meal and were assessed for levels of cholesterol, triglycerides and the apolipoproteins APOA1 and APOB. Our results show that two copies of the rare version of an APOA1 variant, mapping within the gene control region, and just one copy of the rare version of a variant mapping between APOA4 and APOA5 are both linked to a limited response in terms of blood lipid levels after the high-fat challenge. Subjects harboring the less common versions of two APOA4 variants had lower blood levels of APOA1 after the meal. A variant in the gene control region of APOC3 was associated with altered timing of the response of triglyceride levels to the high-fat challenge. We have identified new associations between gene variants of the APOA1/C3/A4/A5 gene cluster and altered after-meal lipid metabolism.

Technical Abstract:
Background: The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state, and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Methods: Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092) and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight, with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 hours after the meal. Total cholesterol (CHOL) and fractions (high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL)), triacylglycerols (TG) in plasma, triacylglycerol-rich lipoproteins (TRL) (large TRL and small TRL), apolipoprotein A-I (APOA1) and apolipoprotein B (APOB) were determined. Results: APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics, but not its magnitude. Conclusions: We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.